Since the discovery of serotonin (5-hydroxytryptamine, 5-HT) over four decades ago, the cumulative results of many diverse studies have indicated that serotonin plays a significant role in the functioning of the mammalian body, both in the central nervous-system and in peripheral systems as well. Morphological studies of the central nervous system have shown that serotonergic neurons, which originate in the brain stem, form a very diffuse system that projects to most areas of the brain and spinal cord. R. A. O'Brien, Serotonin in Mental Abnormalities, 1:41 (1978); H. W. M. Steinbusch, HANDBOOK OF CHEMICAL NEUROANATOMY, Volume 3, Part II, 68 (1984); N. E. Anden, et al., Acta Physiologica Scandinavia, 67:313 (1966). These studies have been complemented by biochemical evidence that indicates large concentrations of 5-HT exist in the brain and spinal cord. H. W. M. Steinbusch, supra.
With such a diffuse system, it is not surprising that 5-HT has been implicated as being involved in the expression of a number of behaviors, physiological responses, and diseases which originate in the central nervous system. These include such diverse areas as sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, schizophrenia, and other bodily states. R. W. Fuller, BIOLOGY OF SEROTONERGIC TRANSMISSION, 221 (1982); D. J. Boullin, SEROTONIN IN MENTAL ABNORMALITIES 1:316 (1978); J. Barchas, et al., Serotonin and Behavior, (1973).
Serotonin plays an important role in peripheral systems as well. For example, approximately 90% of the body's serotonin is synthesized in the gastrointestinal system, and serotonin has been found to mediate a variety of contractile, secretory, and electrophysiologic effects in this system. Serotonin may be taken up by the platelets and, upon platelet aggregation, be released such that the cardiovascular system provides another example of a peripheral network that is very sensitive to serotonin. Given the broad distribution of serotonin within the body, it is understandable that tremendous interest in drugs that affect serotonergic systems exists. In particular, receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, compulsive disorders, schizophrenia, autism, neurodegenerative disorders, such as Alzheimer's disease, Parkinsonism, and Huntington's chorea, and cancer chemotherapy-induced vomiting. M. D. Gershon, et al., THE PERIPHERAL ACTIONS OF 5-HYDROXYTRYPTAMINE, 246 (1989); P. R. Saxena, et al., Journal of Cardiovascular Pharmacology, 15: Supplement 7 (1990).
Serotonin produces its effects on cellular physiology by binding to specialized receptors on the cell surface. Multiple types of receptors exist for many neurotransmitters and hormones, including serotonin. The existence of multiple, structurally distinct serotonin receptors has provided the possibility that subtype-selective pharmacologic agents can be produced. The development of such compounds could result in new and increasingly selective therapeutic agents with fewer side effects, since activation of individual receptor subtypes may function to affect specific actions of the different parts of the central and/or peripheral serotonergic systems.
An example of such specificity can be demonstrated by using the vascular system as an example. In certain blood vessels, stimulation of certain 5-HT receptors on the endothelial cells produces vasodilation while stimulation of certain 5-HT receptors on the smooth muscle cells produces vasoconstriction.
Currently, the major classes of serotonin receptors (5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3, 5-HT.sub.4, 5-HT.sub.5, 5-HT.sub.6, and 5-HT.sub.7) contain some fourteen to eighteen separate receptors that have been formally classified based on their pharmacological or structural differences. For an excellent review of the pharmacological effects and clinical implications of the various 5-HT receptor types, see Glennon, et al., Neuroscience and Behavioral Reviews, 14:35 (1990).! discoveries.
One class of serotonin receptors is the 5-HT.sub.2. Of this class, several subtypes are known to exist. These subtypes include 5-HT.sub.2A, 5-HT.sub.2B and 5-HT.sub.2C. The subtype 5-HT.sub.2A is located in the vascular smooth muscle, platelets, lung, CNS and gastrointestinal tract. This receptor is thought to be associated with vasoconstriction, platelet aggregation, and bronchoconstriction. The 5-HT.sub.2B receptor is localized in the rat lung, stomach fundus, uterus, bladder, and colon. Interesting areas of 5-HT.sub.2B receptor localization in the human include, but are not limited to, the brain and blood vessels. Subtype 5-HT.sub.2C is located in the CNS with a high density in the choroid plexus.
Pollen has long been recognized as a cause of allergic rhinitis commonly called "hay fever". Pollen contains proteases which induce the release of mediators from mast cells, thereby stimulating IgE biosynthesis. The degranulation of mast cells by IgE results in the release of histamine which leads to an inflammatory response which causes congestion, itching, and swelling of sinuses. Degranulation of mast cells can also be caused by inflammatory neuropeptides, like substance P, released from sensory nerves. The histamine released by mast cells following degranulation can activate sensory nerves increasing the release of inflammatory neuropeptides and sending signals to the brain causing sneezing and the spread of the allergic reaction to other, nearby areas, for example, causing watery eyes. In this way, sensory nerves participate in the inflammation process. Many eosinophils are present in allergic patients with nasal mucus and neutrophils are present in patients with infected mucus.
Antihistamines are drugs commonly utilized which, when taken orally, frequently have a sedative effect. Alternatively, nasal sprays containing cromolyn sodium have been effective as cromolyn acts by blocking the reaction of the allergen with tissue mast cells. Cromolyn is not entirely effective, however, as it apparently does not bind to some of the mediators of inflammation or the activators of IgE biosynthesis that stimulate the degranulation of mast cells and the production of histamine from the mast cells.
Inflammation is a non-specific response of tissues to diverse stimuli or insults and results in the release of materials at the site of inflammation that induce pain. It is now recognized that mast cells, neutrophils, T-cells and sensory nerves are implicated in the pathophysiology of inflammatory skin conditions as well as in other physiological disorders. Mast cells provide the greatest source of histamines in acute inflammation, as well as chymases, after degranulation by IgE.
The "common cold" is a time honored phrase used by both physicians and lay persons alike for the identification of acute minor respiratory illness. Since the identification of rhinovirus in 1956, a considerable body of knowledge has been acquired on the etiology and epidemiology of common colds. It is known that the common cold is not a single entity, but rather is a group of diseases caused by members of several families of viruses, including parainfluenza viruses, rhinoviruses, respiratory syncytial viruses, enteroviruses, and coronaviruses. Much work has been performed in characterizing viruses which cause the common cold. In addition, the molecular biology of rhinoviruses, the most important common cold viruses, is understood in great detail. In contrast, progress on the treatment of common colds has been slow despite these advances. While there are now large numbers of compounds that have been found to exhibit antiviral activity against cold viruses in cell culture, antiviral compounds have had limited effectiveness in patients.
Because of the widespread dissatisfaction with the currently marketed treatments for the common cold and allergic rhinitis within the affected population, there exists a need for a more efficacious and safe treatment. The present invention provides such a treatment.